Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function.
Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function.
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DOI：
10.1371/journal.pgen.0010053
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发表时间：
2005-10
期刊：
影响因子：
4.5
通讯作者：
Yoder BK
中科院分区：
文献类型：
--
作者：
Haycraft CJ;Banizs B;Aydin-Son Y;Zhang Q;Michaud EJ;Yoder BK
鞭毛内转运（IFT）蛋白是纤毛组装所必需的，最近已与一些发育过程，如左右轴规范和肢体和神经管图案。遗传学研究表明，IFT蛋白是Sonic hedgehog（Shh）信号传导所必需的，位于Smoothened和Patched膜蛋白的下游，但位于胶质瘤（Gli）转录因子的上游。然而，IFT蛋白在Shh信号转导中的作用以及纤毛在此过程中的重要性仍然未知。在这里，我们提供了深入了解IFT蛋白，Tg 737/北极星的缺陷，影响鼠肢芽中的Shh信号的机制。我们的数据表明，Tg 737的损失导致改变Gli 3处理，废除Gli 3介导的Gli 1转录活性的抑制。与遗传分析得出的结论相反，Gli 1和截短形式的Gli 3（Gli 3R）的活性在分子水平上不受Tg 737突变体的影响，表明Tg 737/Polaris差异参与Gli蛋白的特异性活性。最重要的是，Shh信号传导的负调节因子、融合的抑制因子和三个全长Gli转录因子除了位于细胞核之外还位于纤毛的远端。因此，我们的数据支持纤毛在Gli处理和Shh信号转导中具有直接作用的模型。纤毛是从大多数细胞表面延伸出来的小突起。研究表明，它们在囊性肾病等疾病以及包括肢体在内的许多组织的发育过程中很重要。最近，蛋白质，如北极星，这是需要建立纤毛，已被证明是必不可少的调节声波刺猬（嘘）信号，虽然机制仍然难以捉摸。Shh信号转导的精确调节对于许多组织的正常发育是重要的。Shh通路的过度激活导致严重的发育缺陷，并与某些类型的癌症有关。在肢体中，Shh信号参与手指发育，过量的信号导致额外手指的形成。Shh信号传导的主要目标是胶质瘤（Gli）家族的转录因子，并且已经显示当Shh信号传导被抑制时，Gli 3被加工成缩短的阻遏物形式。Gli转录因子和参与Gli蛋白功能调节的Suppressor of fused在纤毛上的定位表明纤毛可能是通过调节Gli蛋白功能来调节Shh信号转导的重要位点。
Intraflagellar transport (IFT) proteins are essential for cilia assembly and have recently been associated with a number of developmental processes, such as left–right axis specification and limb and neural tube patterning. Genetic studies indicate that IFT proteins are required for Sonic hedgehog (Shh) signaling downstream of the Smoothened and Patched membrane proteins but upstream of the Glioma (Gli) transcription factors. However, the role that IFT proteins play in transduction of Shh signaling and the importance of cilia in this process remain unknown. Here we provide insights into the mechanism by which defects in an IFT protein, Tg737/Polaris, affect Shh signaling in the murine limb bud. Our data show that loss of Tg737 results in altered Gli3 processing that abrogates Gli3-mediated repression of Gli1 transcriptional activity. In contrast to the conclusions drawn from genetic analysis, the activity of Gli1 and truncated forms of Gli3 (Gli3R) are unaffected in Tg737 mutants at the molecular level, indicating that Tg737/Polaris is differentially involved in specific activities of the Gli proteins. Most important, a negative regulator of Shh signaling, Suppressor of fused, and the three full-length Gli transcription factors localize to the distal tip of cilia in addition to the nucleus. Thus, our data support a model where cilia have a direct role in Gli processing and Shh signal transduction. Cilia are small projections extending from the surface of most cells. Research has shown that they are important in diseases such as cystic kidney diseases as well as during the development of many tissues including the limb. More recently, proteins such as Polaris, which is required to build cilia, have been demonstrated to be essential for the regulation of Sonic hedgehog (Shh) signaling, although the mechanism has remained elusive. Precise regulation of Shh signal transduction is important for the proper development of many tissues. Excessive activation of the Shh pathway results in severe developmental defects and has been implicated in certain types of cancer. In the limb, Shh signaling is involved in digit development, and excess signaling leads to the formation of extra digits. The main targets of Shh signaling are the Glioma (Gli) family of transcription factors, and Gli3 has been shown to be processed to a shortened repressor form when Shh signaling is repressed. The localization of the Gli transcription factors and Suppressor of fused, a protein involved in the regulation of Gli protein function, to cilia suggests that the cilia may be an important site for regulation of Shh signal transduction by modulating Gli protein function.
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影响因子：
3.3
作者：
Taulman, PD;Haycraft, CJ;Yoder, BK
通讯作者：
Yoder, BK
DOI：
10.1152/ajprenal.00273.2001
发表时间：
2002-03-01
影响因子：
4.2
作者：
Yoder, BK;Tousson, A;Balkovetz, DF
通讯作者：
Balkovetz, DF
影响因子：
30.8
作者：
HUI, CC;JOYNER, AL
通讯作者：
JOYNER, AL
影响因子：
4.8
作者：
Dunaeva, M;Michelson, P;Toftgard, R
通讯作者：
Toftgard, R
影响因子：
10.5
作者：
MASUYA, H;SAGAI, T;SHIROISHI, T
通讯作者：
SHIROISHI, T